Abstract 11902: Mitochondria-targeted Antioxidant Therapy Improves Age-related Collateral Development With Ischemia Through p53 and Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)

Abstract

Background: Aging is a major factor to decline collateral growth with ischemia, however, the underlying mechanism remains unclear. Methods and Results: We investigated the pathophysiological role of mitochondrial oxidative stress (MOS) in hindlimb ischemia with femoral artery ligation in young mice [8 weeks old (W)] and old mice (80 W) with or without treatment of a mitochondria-targeted antioxidant, MitoTEMPO [180 μg/kg/day, from before operative day 7 to post operative day (POD) 21] infusion using a subcutaneously implanted mini-pump. The recoveries of cutaneous blood flow in hindlimb and capillary density on POD 21 were lower in old mice than in young mice, that were improved in MitoTEMPO-treated old mice. Mitochondrial DNA damage was appeared in ischemic skeletal muscles of old mice, that was eliminated by MitoTEMPO treatment. On POD 2, treatment of MitoTEMPO suppressed the level of p53, the ratio of Bax/Bcl-2 and upregulated the levels of HIF-1α and VEGF in ischemic skeletal muscles of old mice. On POD 21, treatment of MitoTEMPO preserved the level of PGC-1α and its transcriptional factor, estrogen-related receptor α, in ischemic skeletal muscles of old mice. Ischemic soleus of old mice showed lower mitochondrial respiratory control ratio (state 3 respiration/state 4 respiration) on POD 21 than that of young mice, that was recovered in MitoTEMPO-treated old mice (young mice: 3.36±0.08, Old mice: 2.15±0.24 vs. MitoTEMPO-treated old mice: 3.37±0.03, P<0.01). Conclusion: These data suggest that scavenging of MOS recovers collateral growth with ischemia through suppression of p53 and preservation of PGC-1α.